DESCRIPTION: The goal of this research proposal is to understand the synaptic mechanisms by which intracortical feedforward and feedback connections transmit and integrate information. Specifically we will test the hypothesis that feedforward and feedback circuits use diverse excitatory and inhibitory synaptic mechanisms. Preliminary evidence suggests that disynaptic inhibition is much weaker in feedback pathways than in feedforward circuits. Experiments are proposed to confirm and extend these finding and to determine the structural and physiological principles that underlie this asymmetry. In addition, experiments are proposed aimed that are at determining the functional consequences of feedback influences on activity provided by ascending visual pathways. The proposal is inspired by the principal assumption that weak disynaptic inhibition confers unique properties to the feedback circuit. These properties may be similar to those described in developing systems, which are known to have greater synaptic plasticity. Our strong suspicion is that the mechanisms rely on an enhanced activation of NMDA receptors which act to facilitate the transmission of ascending information by influences from backward connections. Such top-down processing has been implicated in a growing list of visual functions such as: providing input about the context in which a stimulus appears, perceptual completion, mediating attentional modulation, feature selection for object discrimination, routing information through cortical areas, and associating behaviorally relevant stimuli. Direct evidence shows that intracortical feedback connections serve as conduit for some these effects. It, therefore, seems reasonable to link this investigation to perceptually important mechanisms. To assess whether forward and feedback circuits operate with distinct inhibitory control mechanisms and to unravel the underlying principles for this difference we will test the following hypotheses:(1) Feedback connections are less strongly inhibiting that forward connections, (2) Inhibition in the feedback circuit is weak because input to inhibitory neurons is weak, (3) feedback interactions are mediated through NMDA receptors, (4) Feedback connection enhance thalamocortical inputs, and (5) Feedback connections enhance intracortical forward inputs. The most prevalent views of the structure and function of cortical microcircuits are derived from thalamocortical and interlaminar circuits of primary visual cortex (Douglas and Martin, 1991). feedback circuits differ from this canonical circuit. Because of this it is expected that the proposed research program will uncover principles of intracortical processing.